Result of Space Particle Monitor (SPM) on-Orbit Demonstration

Space Particle Monitor (SPM) is a compact, lightweight and low-cost radiation measurement device that applies two PIN silicon semiconductor detectors. SPM was developed in the SERVIS (Space Environment Reliability Verification Integrated System) project under the Ministry of Economy, Trade and Industry (METI), and is mounted on JAXA RAPid Innovative payload demonstration Satellite 1 (RAPIS-1) launched in January 2019. We achieved the full success that the discrimination and energy content of electrons, protons, and heavy ions could be observed. This paper reports on-orbit demonstration results of SPM

Gene transfer of tumor necrosis factor inhibitor improves the function of lung allografts

AbstractBackgroundTumor necrosis factor is an important mediator of lung transplant acute rejection. Soluble type I tumor necrosis factor receptor binds to tumor necrosis factor-α and -β and inhibits their function. The objectives of this study were to demonstrate efficient in vivo gene transfer of a soluble type I tumor necrosis factor receptor fusion protein (sTNF-RI-Ig) and determine its effects on lung allograft acute rejection.MethodsThree groups of Fischer rats (n = 6 per group) underwent recipient intramuscular transfection 24 hours before transplantation with saline, 1 × 1010 plaque-forming units of control adenovirus encoding β-galactosidase, or 1 × 1010 plaque-forming units of adenovirus encoding human sTNF-RI-Ig (Ad.sTNF-RI-Ig). One group (n = 6) received recipient intramuscular transfection with 1 × 1010 Ad.sTNF-RI-Ig at the time of transplantation. Brown Norway donor lung grafts were stored for 5 hours before orthotopic lung transplantation. Graft function and rejection scores were assessed 5 days after transplantation. Time-dependent transgene expression in muscle, serum, and lung grafts were evaluated by using enzyme-linked immunosorbent assay of human soluble type I tumor necrosis factor receptor.ResultsRecipient intramuscular transfection with 1 × 1010 plaque-forming units of Ad.sTNF-RI-Ig significantly improved arterial oxygenation when delivered 24 hours before transplantation compared with saline, β-galactosidase, and Ad.sTNF-RI-Ig transfection at the time of transplantation (435.8 ± 106.6 mm Hg vs 142.3 ± 146.3 mm Hg, 177.4 ± 153.7 mm Hg, and 237.3 ± 185.2 mm Hg; P = .002, .005, and .046, respectively). Transgene expression was time dependent, and there was a trend toward lower vascular rejection scores (P = .066) in the Ad.sTNF-RI-Ig group transfected 24 hours before transplantation.ConclusionsRecipient intramuscular Ad.sTNF-RI-Ig gene transfer improves allograft function in a well-established model of acute rejection. Maximum benefit was observed when transfection occurred 24 hours before transplantation

Immunochemotherapy of gastric cancer with levamisole.

In 156 cases of gastric cancer, levamisole (LMS) was administered at a daily dose of 150 mg for three consecutive days every other week. The administration was started 3 days before operation. This medication was repeated for more than one month. The survival rate up to two years after surgery was studied. The survival rate was not affected in patients with Stage I and II gastric cancer, but in patients with Stage III, the difference in the survival rate between the LMS group and the control group was significantly higher than that in the control group (p less than 0.05). In patients with Stage IV, the survival rate in the LMS group was higher than that in the control group although the difference was not significant. In patients of Stage III and IV, the effect of LMS on the survival rate was highest in cases with curative resection (p less than 0.01). In cases with noncurative resection, the difference between the LMS group and the control group was greatest (24.4%) 12 months after surgery but not significant (p less than 0.5), and also in cases without resection the difference between the two groups was greatest (20.3%) 12 months after surgery but not significant (p less than 0.2).</p

Functional complexes between YAP2 and ZO-2 are PDZ domain-dependent, and regulate YAP2 nuclear localization and signalling

he Hippo pathway regulates the size of organs by controlling two opposing processes: proliferation and apoptosis. YAP2 (Yes kinase-associated protein 2), one of the three isoforms of YAP, is a WW domain-containing transcriptional co-activator that acts as the effector of the Hippo pathway in mammalian cells. In addition to WW domains, YAP2 has a PDZ-binding motif at its C-terminus. We reported previously that this motif was necessary for YAP2 localization in the nucleus and for promoting cell detachment and apoptosis. In the present study, we show that the tight junction protein ZO (zonula occludens)-2 uses its first PDZ domain to form a complex with YAP2. The endogenous ZO-2 and YAP2 proteins co-localize in the nucleus. We also found that ZO-2 facilitates the nuclear localization and pro-apoptotic function of YAP2, and that this activity of ZO-2 is PDZ-domain-dependent. The present paper is the first report on a PDZ-based nuclear translocation mechanism. Moreover, since the Hippo pathway acts as a tumour suppressor pathway, the YAP2-ZO-2 complex could represent a target for cancer therapy

Development of a screening system for central visual field using the eye-tracking device\n

　Background: Visual field test with gaze movements do not require a subjective response because they are based on reflexive movements. In this study, we developed a visual field test system with gaze movements to perform a central visual field screening, and then examined the reproducibility of the measurements in healthy adult volunteers.　Methods: We examined 30 right eyes of 30 healthy volunteers (mean age, 22.7 ± 5.2 years) with a best-corrected visual acuity of at least 20/20. Gazefinder, an eye-tracking device, was used to measure gaze movements. Subjects with refractive correction were asked to follow a white target presented on a monitor. If a subject can accurately perform eye tracking with respect to the visual target, visual field with gaze movements measurements are theoretically possible in eight directions (horizontal/vertical to 15.3° and oblique to 21.5° ). After a total of three measurements, the data were quantified using analysis software (CreateChart). Finally, the intraclass correlation coefficients of the measurement values were obtained.　Results: The difference between theoretical and actual measurement values, which is thought to reflect gaze accuracy, were –0.1° ± 0.9° for upper, –0.6° ± 1.0° for upper right, –0.2° ± 1.0° for right, –0.8° ± 0.9° for lower right, –0.5° ± 0.7° for lower, –0.5° ± 0.9° for lower left, –0.6 ° ± 0.5 ° for left, and –0.6 ° ± 0.5 ° for upper left. No significant differences were found among the eight directions, and gaze accuracy was high, at within 1°. The intraclass correlation coefficients were 0.6 or higher in each direction (P < 0.01), indicating high repeatability.　Conclusions: In the traditional method for measuring visual field with gaze movements, the fixation point of view needs to be reset for each gaze movement. On the other hand, the system developed in this study has the advantage of not requiring eye movements to return to the fixation point. The present findings indicate that our newly developed system is a useful device when standard perimetry is difficult to measure

Chest Wall Invasion by Peripheral Lung Cancer: Preoperative Assessment with Respiratory Dynamic MRI

Purpose: The purpose of our study was to evaluate the usefulness of dynamic cine MRI during respiration in the assessment of chest wall invasion by lung cancer. Materials and Methods: We prospectively performed respiratory dynamic MRI in 34 patients with peripheral lung cancer, in whom the presence of chest wall invasion was indeterminate on CT. Sequential images were obtained during respiration by using fast spoiled GRASS (SPGR) sequence, and were analyzed in cine mode display. Results: In all 23 patients with free movement of the tumor along the chest wall on respiratory dynamic cine MRI, no chest wall invasion was found at surgery (negative predictive value 100%). In eleven patients with fixation of the tumor to the chest wall, invasion was confirmed pathologically in five patients, while benign fibrous adhesion was found in six. Conclusion: Although it has some limitations, dynamic cine MRI during respiration is useful in evaluating chest wall invasion in patients with lung cancer, particularly when CT findings are indeterminate

WW Domains of the Yes-Kinase-Associated-Protein (YAP) Transcriptional Regulator Behave as Independent Units with Different Binding Preferences for PPxY Motif-Containing Ligands

YAP is a WW domain-containing effector of the Hippo tumor suppressor pathway, and the object of heightened interest as a potent oncogene and stemness factor. YAP has two major isoforms that differ in the number of WW domains they harbor. Elucidating the degree of co-operation between these WW domains is important for a full understanding of the molecular function of YAP. We present here a detailed biophysical study of the structural stability and binding properties of the two YAP WW domains aimed at investigating the relationship between both domains in terms of structural stability and partner recognition. We have carried out a calorimetric study of the structural stability of the two YAP WW domains, both isolated and in a tandem configuration, and their interaction with a set of functionally relevant ligands derived from PTCH1 and LATS kinases. We find that the two YAP WW domains behave as independent units with different binding preferences, suggesting that the presence of the second WW domain might contribute to modulate target recognition between the two YAP isoforms. Analysis of structural models and phage-display studies indicate that electrostatic interactions play a critical role in binding specificity. Together, these results are relevant to understand of YAP function and open the door to the design of highly specific ligands of interest to delineate the functional role of each WW domain in YAP signaling.This work was supported by the Spanish Ministry of Education and Science [grant BIO2009-13261-CO2], the Spanish Ministry of Economy and Competitivity [grant BIO2012-39922-CO2] including FEDER (European Funds for Regional Development) funds and the Governement of Andalusia [grant CVI-5915]. Marius Sudol was supported by PA Breast Cancer Coalition Grants (#60707 and #920093) plus the Geisinger Clinic

A Potent Inhibitor of SIK2, 3, 3′, 7-Trihydroxy-4′-Methoxyflavon (4′-O-Methylfisetin), Promotes Melanogenesis in B16F10 Melanoma Cells

Flavonoids, which are plant polyphenols, are now widely used in supplements and cosmetics. Here, we report that 4′-methylflavonoids are potent inducers of melanogenesis in B16F10 melanoma cells and in mice. We recently identified salt inducible kinase 2 (SIK2) as an inhibitor of melanogenesis via the suppression of the cAMP-response element binding protein (CREB)-specific coactivator 1 (TORC1). Using an in vitro kinase assay targeting SIK2, we identified fisetin as a candidate inhibitor, possibly being capable of promoting melanogenesis. However, fisetin neither inhibited the CREB-inhibitory activity of SIK2 nor promoted melanogenesis in B16F10 melanoma cells. Conversely, mono-methyl-flavonoids, such as diosmetin (4′-O-metlylluteolin), efficiently inhibited SIK2 and promoted melanogenesis in this cell line. The cAMP-CREB system is impaired in Ay/a mice and these mice have yellow hair as a result of pheomelanogenesis, while Sik2+/−; Ay/a mice also have yellow hair, but activate eumelanogenesis when they are exposed to CREB stimulators. Feeding Sik2+/−; Ay/a mice with diets supplemented with fisetin resulted in their hair color changing to brown, and metabolite analysis suggested the presence of mono-methylfisetin in their feces. Thus, we decided to synthesize 4′-O-methylfisetin (4′MF) and found that 4′MF strongly induced melanogenesis in B16F10 melanoma cells, which was accompanied by the nuclear translocation of TORC1, and the 4′-O-methylfisetin-induced melanogenic programs were inhibited by the overexpression of dominant negative TORC1. In conclusion, compounds that modulate SIK2 cascades are helpful to regulate melanogenesis via TORC1 without affecting cAMP levels, and the combined analysis of Sik2+/− mice and metabolites from these mice is an effective strategy to identify beneficial compounds to regulate CREB activity in vivo